Herpes viruses inflict a wide range of diseases against humans and animals. For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the Epstein-Barr virus (EBV) causes infectious mononucleosis.
Inhibitors of herpesvirus ribonucleotide reductase have been found to exhibit antiherpes activity. Indeed, several reports of peptide derivatives having inhibitory activity against the herpesvirus ribonucleotide reductase enzyme have been reported. For example, see the following references:
E. A. Cohen et al., U.S. Pat. No. 4,795,740, Jan. 3, 1989, PA1 R. Freidinger et al., U.S. Pat. 4,814,432, Mar. 21, 1989, PA1 P. Gaudreau et al., J. Med. Chem. 1990, 33, 723, PA1 J. Adams et al., European patent application 411,334, published Feb. 6, 1991, PA1 R. L. Tolman et al., European patent application 412, 595, published Feb. 13, 1991, PA1 L. L. Chang et al., Bioorg. Med. Chem. Lett. 1992, 2, 1702, PA1 P. L. Beaulieu et al., European patent application 560 267, published Sep. 15, 1993, PA1 N. Moss et al., J. Med.Chem. 1993, 36, 3005, PA1 R. Deziel and N. Moss, European patent application 618 226, published Oct. 5, 1994, PA1 N. Moss et al., Bioorg. Med. Chem. 1994, 2, 959, PA1 M. Liuzzi et al., Nature 1994, 372, 695, PA1 N. Moss et al., J. Med. Chem. 1995, 38, 3617, and N. Moss et al., J. Med. Chem. 1996, 39, 4173.
It has recently been demonstrated that replacement of an aspartic acid residue with an (S)-.alpha.-amino-1-carboxycyclopentaneacetic acid residue in this type of inhibitor improved potency 50-fold (N. Moss, et al., Bioorg. Med. Chem. 1994, 2, 959). Apparently, the cyclopentyl group improved inhibitor potency by strongly favoring a specific conformation, namely the S configuration of the aspartic acid side chain, that facilitated binding the enzyme. This modification also proved vital in obtaining inhibitors with good antiviral activity in vitro and in vivo (M. Liuzzi et al., Nature 1994, 372, 695; N. Moss et al., J. Med. Chem. 1995, 38, 3617). The critical importance of the (S)-.alpha.-amino-1-carboxycyclopentaneacetic acid moiety makes a facile enantioselective synthesis of this amino acid derivative highly desirable.
N. Moss et al., J. Med. Chem. 1995, 38, 3617 disclose a procedure for the synthesis of a precursor of (S)-.alpha.-amino-1-carboxycyclopentaneacetic acid. This derivative could readily be incorporated into peptide and peptidomimetic inhibitors. However the synthesis of this precursor requires carefully controlled low temperature conditions (-78.degree. C.) and purification by chromatography. These requirements can be impractical for the large scale preparation of this compound.
To circumvent these problems, a synthesis that would avoid low temperature reactions and difficult purifications is required. Therefore, efficient and low cost methods which are amenable to scale-up are needed for the preparation of (S)-.alpha.-amino-1-carboxycyclopentaneacetic acid.
The process disclosed herein fulfills these needs.
The present process, and key intermediate compounds prepared by the present process, can be distinguished readily from the prior art. The intermediate compounds of the process possess novel chemical structures.